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Ascl2-Dependent Cell Dedifferentiation Drives Regeneration of Ablated Intestinal Stem Cells.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2020-02-14 , DOI: 10.1016/j.stem.2019.12.011
Kazutaka Murata 1 , Unmesh Jadhav 1 , Shariq Madha 2 , Johan van Es 3 , Justin Dean 4 , Alessia Cavazza 1 , Kai Wucherpfennig 5 , Franziska Michor 4 , Hans Clevers 3 , Ramesh A Shivdasani 6
Affiliation  

Ablation of LGR5+ intestinal stem cells (ISCs) is associated with rapid restoration of the ISC compartment. Different intestinal crypt populations dedifferentiate to provide new ISCs, but the transcriptional and signaling trajectories that guide this process are unclear, and a large body of work suggests that quiescent "reserve" ISCs contribute to regeneration. By timing the interval between LGR5+ lineage tracing and lethal injury, we show that ISC regeneration is explained nearly completely by dedifferentiation, with contributions from absorptive and secretory progenitors. The ISC-restricted transcription factor ASCL2 confers measurable competitive advantage to resting ISCs and is essential to restore the ISC compartment. Regenerating cells re-express Ascl2 days before Lgr5, and single-cell RNA sequencing (scRNA-seq) analyses reveal transcriptional paths underlying dedifferentiation. ASCL2 target genes include the interleukin-11 (IL-11) receptor Il11ra1, and recombinant IL-11 enhances crypt cell regenerative potential. These findings reveal cell dedifferentiation as the principal means for ISC restoration and highlight an ASCL2-regulated signal that enables this adaptive response.

中文翻译:

Ascl2 依赖性细胞去分化驱动消融的肠道干细胞再生。

LGR5+ 肠干细胞 (ISC) 的消融与 ISC 隔室的快速恢复有关。不同的肠隐窝群体去分化以提供新的 ISC,但指导这一过程的转录和信号轨迹尚不清楚,大量工作表明静止的“储备”ISC 有助于再生。通过计算 LGR5+ 谱系追踪和致死性损伤之间的时间间隔,我们表明 ISC 再生几乎完全可以通过去分化来解释,吸收和分泌祖细胞的贡献。ISC 限制性转录因子 ASCL2 赋予静息 ISC 可测量的竞争优势,并且对于恢复 ISC 隔室至关重要。再生细胞在 Lgr5 前几天重新表达 Ascl2,和单细胞 RNA 测序 (scRNA-seq) 分析揭示了去分化背后的转录路径。ASCL2 靶基因包括白细胞介素 11 (IL-11) 受体 Il11ra1,重组 IL-11 增强隐窝细胞再生潜能。这些发现揭示了细胞去分化是 ISC 恢复的主要手段,并强调了 ASCL2 调节信号能够实现这种适应性反应。
更新日期:2020-02-20
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